Blocking c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors

Yi Du, Hirohito Yamaguchi, Yongkun Wei, Jennifer L. Hsu, Hung Ling Wang, Yi Hsin Hsu, Wan Chi Lin, Wen Hsuan Yu, Paul G. Leonard, Gilbert R. Lee, Mei Kuang Chen, Katsuya Nakai, Ming Chuan Hsu, Chun Te Chen, Ye Sun, Yun Wu, Wei Chao Chang, Wen Chien Huang, Chien Liang Liu, Yuan Ching ChangChung Hsuan Chen, Morag Park, Philip Jones, Gabriel N. Hortobagyi, Mien Chie Hung

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapeutics for many diseases, including cancer, in clinical trials. One PARP inhibitor, olaparib (Lynparza, AstraZeneca), was recently approved by the FDA to treat ovarian cancer with mutations in BRCA genes. BRCA1 and BRCA2 have essential roles in repairing DNA double-strand breaks, and a deficiency of BRCA proteins sensitizes cancer cells to PARP inhibition. Here we show that the receptor tyrosine kinase c-Met associates with and phosphorylates PARP1 at Tyr907 (PARP1 pTyr907 or pY907). PARP1 pY907 increases PARP1 enzymatic activity and reduces binding to a PARP inhibitor, thereby rendering cancer cells resistant to PARP inhibition. The combination of c-Met and PARP1 inhibitors synergized to suppress the growth of breast cancer cells in vitro and xenograft tumor models, and we observed similar synergistic effects in a lung cancer xenograft tumor model. These results suggest that the abundance of PARP1 pY907 may predict tumor resistance to PARP inhibitors, and that treatment with a combination of c-Met and PARP inhibitors may benefit patients whose tumors show high c-Met expression and who do not respond to PARP inhibition alone.

Original languageEnglish (US)
Pages (from-to)194-201
Number of pages8
JournalNature Medicine
Volume22
Issue number2
DOIs
StatePublished - Feb 1 2016
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Du, Y., Yamaguchi, H., Wei, Y., Hsu, J. L., Wang, H. L., Hsu, Y. H., Lin, W. C., Yu, W. H., Leonard, P. G., Lee, G. R., Chen, M. K., Nakai, K., Hsu, M. C., Chen, C. T., Sun, Y., Wu, Y., Chang, W. C., Huang, W. C., Liu, C. L., ... Hung, M. C. (2016). Blocking c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors. Nature Medicine, 22(2), 194-201. https://doi.org/10.1038/nm.4032